POS0674 RISK FACTORS FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS AGED ≥50 YEARS WITH RHEUMATOID ARTHRITIS AND ≥1 ADDITIONAL CARDIOVASCULAR RISK FACTOR: A POST HOC ANALYSIS OF ORAL SURVEILLANCE
Authors: C. Charles-Schoeman, M. H. Buch, M. Dougados, D. L. Bhatt, J. T. Giles, S. R. Ytterberg, G. G. Koch, I. Vranic, J. Wu, C. Wang, S. Menon, J. L. Rivas, A. Yndestad, C. A. Connell, Z. Szekanecz
Journal: Annals of the Rheumatic Diseases (2022)

Background ORAL Surveillance ( NCT02092467 ) was a post-approval safety study of tofacitinib vs TNF inhibitors (TNFi) in rheumatoid arthritis (RA) patients (pts) aged ≥50 yrs with ≥1 additional cardiovascular (CV) risk factor and an inadequate response to methotrexate (MTX). Objectives To identify independent risk factors for major adverse CV events (MACE) in ORAL Surveillance. Methods Pts on stable MTX were randomised 1:1:1 to receive tofacitinib 5 or 10 mg twice daily (BID) or a TNFi (adalimumab 40 mg every 2 weeks or etanercept 50 mg once weekly). Incidence rates (IRs; pts with first events/100 pt-yrs) and hazard ratios (HRs; tofacitinib vs TNFi) were assessed for adjudicated MACE (total/fatal/non-fatal), sudden cardiac death, and total/fatal/non-fatal myocardial infarction (MI) and stroke. Post hoc univariate Cox model analyses identified potentially independent baseline (BL) risk factors for MACE across treatments; those with p&lt;0.10 were entered into a multivariate Cox model using backward selection (p&lt;0.10 stay criteria). MACE HRs were produced for subgroups for BL risk factors with p&lt;0.05 in the final multivariate Cox model. Results 4362 pts were included (tofacitinib 5 mg BID, n=1455; tofacitinib 10 mg BID, n=1456; TNFi, n=1451). IRs for total/fatal/non-fatal MACE, sudden cardiac death, and total/non-fatal MI were higher with tofacitinib vs TNFi (Table 1). Fatal MI and stroke (including fatal/non-fatal events) IRs were similar across treatments (Table 1). Total MACE and MI IRs and risk were higher with tofacitinib vs TNFi (HRs &gt;1) and higher for non-fatal MI for tofacitinib 5 mg BID (Table 1). Current smoking, aspirin use, history of chronic lung disease, history of diabetes, male sex and older age were BL risk factors for MACE. While MACE risk was generally higher with tofacitinib vs TNFi across all BL risk factors, increased risk was clearest in current/past smokers (vs never smoked) and aspirin users (vs non-users) (Figure 1). When age and smoking status were considered in combination, pts aged ≥65 yrs or who had ever smoked had a particularly elevated MACE risk vs never smokers aged ≥50–&lt;65 yrs (Figure 1). Table 1. MACE, MI and stroke IRs (pts with first events/100 pt-yrs; 95% CI) and HRs (tofacitinib vs TNFi; 95% CI) Tofacitinib 5 mg BID(N=1455) Tofacitinib 10 mg BID(N=1456) TNFi(N=1451) n IR HR n IR HR n IR (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) MACE 47 0.91 1.24 51 1.05 1.43 37 0.73 (0.67, 1.21) (0.81, 1.91) (0.78, 1.38) (0.94, 2.18) (0.52, 1.01) Fatal MACE 14 0.27 1.14 19 0.39 1.63 12 0.24 (0.15, 0.45) (0.53, 2.47) (0.23, 0.60) (0.79, 3.36) (0.12, 0.41) Non-fatal MACE 33 0.64 1.29 32 0.66 1.33 25 0.50 (0.44, 0.90) (0.77, 2.17) (0.45, 0.93) (0.79, 2.24) (0.32, 0.73) Sudden cardiac death 10 0.19 1.22 13 0.26 1.67 8 0.16 (0.09, 0.35) (0.48, 3.10) (0.14, 0.45) (0.69, 4.04) (0.07, 0.31) MI 19 0.37 1.69 19 0.39 1.80 11 0.22 (0.22, 0.57) (0.80, 3.55) (0.23, 0.61) (0.85, 3.77) (0.11, 0.39) Fatal MI 0 0 NI 3 0.06 1.03 3 0.06 (0.00, 0.07) (0.01, 0.18) (0.21, 5.11) (0.01, 0.17) Non-fatal MI 19 0.37 2.32 16 0.33 2.08 8 0.16 (0.22, 0.57) (1.02, 5.30) a (0.19, 0.53) (0.89, 4.86) (0.07, 0.31) Stroke 18 0.35 1.03 18 0.37 1.10 17 0.34 (0.21, 0.55) (0.53, 2.00) (0.22, 0.58) (0.57, 2.13) (0.20, 0.54) Fatal stroke 4 0.08 NI 2 0.04 NI 0 0.00 (0.02, 0.20) (0.00, 0.15) (0.00, 0.07) Non-fatal stroke 14 0.27 0.80 16 0.33 0.97 17 0.34 (0.15, 0.45) (0.40, 1.63) (0.19, 0.53) (0.49, 1.93) (0.20, 0.54) a HR 95% CI excludes 1. Data collected after pts who were randomised to tofacitinib 10 mg BID had their dose reduced to 5 mg. BID were included in the tofacitinib 10 mg BID group . HRs (95% CI) were not informative when one of the treatments in the comparison had 0 events. Risk period was defined as time from first dose to last dose +60 days or to the last contact date, whichever was earlier. CI, confidence interval; NI, non-informative Conclusion MACE IRs and risk were higher with tofacitinib vs TNFi in ORAL Surveillance. BL risk factor findings could aid identification of RA pts with potentially highest risk for MACE, with a view to informing treatment decisions. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by Kirsten Woollcott, CMC Connect, and funded by Pfizer Inc. Disclosure of Interests Christina Charles-Schoeman Consultant of: AbbVie, Gilead Sciences, Pfizer Inc and Sanofi-Regeneron, Grant/research support from: AbbVie, Bristol-Myers Squibb and Pfizer Inc, Maya H Buch Speakers bureau: AbbVie, Consultant of: AbbVie, Eli Lilly, Gilead Sciences, MSD, Pfizer Inc and Roche, Grant/research support from: Pfizer Inc, Roche and UCB, Maxime Dougados Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer Inc, Roche and UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer Inc, Roche and UCB, Deepak L Bhatt Grant/research support from: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eli Lilly, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Medtronic, MyoKardia, Novo Nordisk, Owkin, Pfizer Inc, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic and The Medicines Company, Jon T Giles Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Genentech, Gilead Sciences and UCB, Grant/research support from: Pfizer Inc, Steven R. Ytterberg Consultant of: Corbus Pharmaceuticals, Kezar Life Sciences and Pfizer Inc, Gary G Koch Shareholder of: IQVIA, Grant/research support from: AbbVie, Acceleron, Amgen, Arena, AstraZeneca, Cytokinetics, Eli Lilly, Gilead, GSK, Huya Bioscience International, Johnson &amp; Johnson, Landos Biopharma, Merck, Momentum, Novartis, Otsuka, Pfizer Inc, Sanofi and vTv Therapeutics, Employee of: University of North Carolina at Chapel Hill, Ivana Vranic Shareholder of: Pfizer Inc, Employee of: Pfizer Ltd, Joseph Wu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cunshan Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Sujatha Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Jose L. Rivas Shareholder of: Pfizer Inc, Employee of: Pfizer SLU, Arne Yndestad Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Carol A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Zoltán Szekanecz Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Paid instructor for: AbbVie, Eli Lilly, Gedeon Richter, Novartis, Pfizer Inc and Roche, Consultant of: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi